Activation of oxidative stress signaling that is implicated in apoptosis with a mouse model of diabetic embryopathy

Yang, Peixin; Zhao, Zhiyong; Reece, E. Albert

doi:10.1016/j.ajog.2007.06.070

Cited by 93 publications

(115 citation statements)

References 35 publications

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“…Beside NTDs, maternal diabetes induces more than 20% heart defects in C57BL/6J background (28). By realizing this conflict, we have extensively characterized and validated our models in this particular background by including surgical (anesthesia) controls and insulin-treated diabetic controls (54).…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting was performed as described previously (24,54,55). Briefly, E8.75 embryos from different experimental groups were sonicated in 80 l of ice-cold lysis buffer (20 mM Tris·HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 10 mM NaF, 2 mM Na-orthovanadate, 1 mM PMSF, and 1% Triton 100) containing a protease inhibitor cocktail (Sigma, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

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Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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114

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isting maternal diabetes increases the risk of neural tube defects (NTDs). The mechanism underlying maternal diabetes-induced NTDs is not totally defined, and its prevention remains a challenge. Autophagy, an intracellular process to degrade dysfunction protein and damaged cellular organelles, regulates cell proliferation, differentiation, and apoptosis. Because autophagy impairment causes NTDs reminiscent of those observed in diabetic pregnancies, we hypothesize that maternal diabetes-induced autophagy impairment causes NTD formation by disrupting cellular homeostasis, leading to endoplasmic reticulum (ER) stress and apoptosis, and that restoration of autophagy by trehalose, a natural disaccharide, prevents diabetes-induced NTDs. Embryos from nondiabetic and type 1 diabetic mice fed with or without 2 or 5% trehalose water were used to assess markers of autophagy, ER stress, and neurogenesis, numbers of autophagosomes, gene expression that regulates autophagy, NTD rates, indices of mitochondrial dysfunction, and neuroepithelial cell apoptosis. Maternal diabetes suppressed autophagy by significantly reducing LC3-II expression, autophagosome numbers, and GFP-LC3 punctate foci in neuroepithelial cells and by altering autophagy-related gene expression. Maternal diabetes delayed neurogenesis by blocking Sox1 neural progenitor differentiation. Trehalose treatment reversed autophagy impairment and prevented NTDs in diabetic pregnancies. Trehalose resolved homeostatic imbalance by correcting mitochondrial defects, dysfunctional proteins, ER stress, apoptosis, and delayed neurogenesis in the neural tubes exposed to hyperglycemia. Our study demonstrates for the first time that maternal diabetes suppresses autophagy in neuroepithelial cells of the developing neural tube, leading to NTD formation, and provides evidence for the potential efficacy of trehalose as an intervention against hyperglycemia-induced NTDs. diabetic embryopathy; autophagy; trehalose; neurogenesis; neural tube defects PREGESTATIONAL DIABETES significantly increases the risk of neural tube defects (NTDs), also known as diabetic embryopathy. There are three to 10 times more NTDs in the offspring of diabetic mothers than in those of nondiabetic mothers (3, 9, 36). Because optimal glycemic control is difficult to achieve and maintain, and even transient exposure to diabetes causes NTDs, maternal diabetes-induced NTDs are significant health problems for both the mother and child. The seriousness of these relationships is emphasized by the upsurge in diabetic pregnancies; nearly 3 million American women and 70 million women worldwide of reproductive age (18 -44 yr) have diabetes today, and this number is expected double by 2030. Although diabetic mellitus is a complex metabolic disease, hyperglycemia is the sole mediator of diabetes teratogenicity. Indeed, clinical studies have revealed a strong correlation between the degree of maternal hyperglycemia and the rate and severity of birth defects (15, 29). When whole rodent embryos are cultured in high concentra...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

114

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“…Briefly, 10-wk-old WT and Ask1 Ϫ/Ϫ female mice were intravenously injected daily with 75 mg/kg STZ over 2 days to induce diabetes. Using STZ to induce diabetes is not a complicating factor because STZ is cleared from the bloodstream rapidly (serum half-life, 15 min) (36), and pregnancy is not established until 1-2 wk after STZ injection (59). Diabetes was defined as a 12-h fasting blood glucose level of Ն14 mM.…”

Section: Mice and Reagentsmentioning

confidence: 99%

“…Maternal diabetes induces oxidative stress in the developing embryo (6,9,26,45,48,53,58,59) and activates apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK) kinase, in neurulation stage embryos (47,57). ASK1 responds to oxidative stress and induces apoptosis via the activation of c-Jun NH 2 -terminal kinase 1/2 (JNK) and/or p38 MAPK (42).…”

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confidence: 99%

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Wang¹,

Wu²,

Quon³

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…PAX-3 is of fundamental importance for the development of the neural tube. In its absence, p53 and other proapoptotic proteins lead to cell apoptosis and cause neural tube defects as well as dysmorphologies (35,36). On the other hand, hyperinsulinism has also been linked independently to the development of fetal malformations.…”

Section: Discussionmentioning

confidence: 99%

Increasing Maternal Body Mass Index Is Associated With Fetal Defects

Mackelenbergh¹,

Marotte²,

Alkatout³

et al. 2016

IJWHR

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IntroductionThe incidence of obesity is constantly rising and is developing into a relevant economic and public health concern. According to the World Health Organization (WHO) 1.4 billion people in the world suffered from obesity in 2008. Of these 0.3 billion were women including those of childbearing age. In pregnancy, obesity increases the risks both for the mother and fetus. Maternal risks are thromboembolism, gestational diabetes, preeclampsia, hypertension and urogenital infections (1-3). Moreover, an increased maternal body mass index (BMI) has been shown to be a risk factor for spontaneous abortion and intrauterine fetal death (2,4). A recent study demonstrated that obese women who suffered two or more abortions tended to have a higher incidence of euploid abortions (5). Regarding delivery, a higher rate of cesarean sections has been described in obese women with an increase in surgical and postoperative complications (3,6). Children of women with a high BMI are more likely to be delivered preterm with a subsequent need for neonatal intensive care treatment (7,8). In addition, maternal obesity is linked to high infant birth weight, subsequent complications during delivery and an increased incidence of children suffering from a metabolic syndrome in their later lives (9,10). However, the occurrence of congenital fetal anomalies has also been associated with obesity in pregnant women. A meta-analysis of 12 studies could confirm an association between maternal obesity and an increased risk of neural tube defects (11), whereas another meta-analysis of 18 studies showed an association between the incidence of fetal hydrocephaly, cardiovascular anomalies, cleft palate, anorectal atresia and limb reduction anomalies (12). Interestingly, the risk of gastroschisis was significantly reduced in obese mothers. On the other hand, congenital anomalies are a major risk factor for perinatal and infant death (13). Prenatal ultrasound scans are utilized to detect congenital malformations in pregnancy. The effect of maternal overweight and obesity on the sensitivity of ultrasound diagnostics has been reported previously. Aagaard-Tillery et al described that maternal obesity significantly decreased the likelihood of sonographic detection of common anomalies in 8555 pregnancies with available BMI (14). This would lead to the assumption that obese women not only tend to have a higher risk of having children with congenital anomalies but also suffer from lower detection rates which has implications on antenatal counseling in this group (15). The aim of this retrospective case-control study was to investigate the association between maternal BMI and con- AbstractObjectives: To test the hypothesis, that increasing maternal weight is directly related to the incidence of fetal anomalies, to rank anomalies according to their frequency and to establish detection rates for the various anomalies with increasing body mass index (BMI). Materials and Methods: Retrospective single center matched case control study, analysis of the associa...

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Activation of oxidative stress signaling that is implicated in apoptosis with a mouse model of diabetic embryopathy

Cited by 93 publications

References 35 publications

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Increasing Maternal Body Mass Index Is Associated With Fetal Defects

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